Abstract
Implicated in autoimmune encephalitis, neuromyotonia and genetic forms of autism, here we report that contactin-associated protein-like 2 (CNTNAP2) contains a potential autoepitope within the extracellular region. CNTNAP2 sequence-similar regions (CSSRs) from human pathogens were identified. Sera from autistic and control children were obtained and analyzed for the presence of antibodies able to bind CSSRs. One such candidate CSSR was evaluated for evidence of autoimmune responses to CNTNAP2 in a mouse model of acute infection. Autistic and control children sera contained antibodies able to discrete regions of CNTNAP2. In a murine model of acute infection, a CSSR derived from the N-terminal extracellular region of CNTNAP2 resulted in anti-CNTNAP2 antibody production, proinflammatory cytokine elevation, cerebellar and cortical white matter T-cell infiltration as well as motor dysfunction. Taken together, these data suggest that CNTNAP2 contains a potential autoepitope within the extracellular region.
Highlights
Molecular mimicry is a process whereby an amino acid sequence-similar region, or shapesimilar region, of a protein or other non-protein compound from an offending pathogen or other agent induces the production of adaptive immune system elements such as antibodies and/or T-cell receptors capable of cross-reacting with proteins or other compounds of the host
Taken together, these data suggest that contactin-associated protein-like 2 (CNTNAP2) contains a potential autoepitope within the extracellular region
To test the hypothesis that linear protein sequences from known human viral and bacterial pathogens could be useful in predicting potential autoepitopes on human CNTNAP2 we screened for CNTNAP2 sequence-similar regions (CSSR) by comparison of human and mouse CNTNAP2 proteins against known bacterial and viral protein databases using NCBI Protein-Basic Local Alignment Search Tool (BLAST) [25] (Table 1)
Summary
Molecular mimicry is a process whereby an amino acid sequence-similar region, or shapesimilar region, of a protein or other non-protein compound from an offending pathogen or other agent induces the production of adaptive immune system elements such as antibodies and/or T-cell receptors capable of cross-reacting with proteins or other compounds of the host This pathological mechanism is thought to be involved in several conditions including: paraneoplastic cerebellar syndrome [1], autoimmune neuromyotonia [2], multiple sclerosis and related disorders [3,4], NMDAR encephalitis, and other autoimmune encephalopathies [5,6,7] as well as some developmental disorders including autism spectrum disorders [8,9,10,11,12]. Given its involvement in autoantibody-mediated neuroinflammatory disease, the investigations presented here evaluated CNTNAP2 for potential autoepitopes through a bioinformatics approach coupled with characterization of human CNTNAP2 binding antibodies from autistic and non-autistic children, and evaluation of a pathogen protein with similar linear protein sequences to human CNTNAP2 in a mouse model of acute infection
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